High Stroke Risk Transient After Infection in Kids

Pauline Anderson

August 20, 2014

The strong effect of minor infections on risk of stroke in children appears to be short lived, new research shows.

While a previous study by the same authors showed that minor infections are an independent risk factor for pediatric ischemic stroke, this new research adds information regarding the timing between the infection and the stroke, and the effect of cumulative infections.

According to this recent analysis, the risk is highest during the 3 days following a doctor's visit for an infection, after which it rapidly diminishes. This suggests that an infection has an acute and powerful effect on stroke risk that is "very transient," said study author Heather Fullerton, MD, director, Pediatric Stroke and Cerebrovascular Disease Center, University of California at San Francisco.

The research, published online August 20 in Neurology, also suggests that unlike in adults, there is little effect of cumulative infections in children.

Minor Infections

The researchers used the Kaiser Pediatric Stroke Study, which represents about 2.5 million children enrolled between 1993 and 2007 in Kaiser Permanente Northern California (KPNC), the largest nonprofit managed care organization in the United States.

From medical records, they identified 102 children, older than 28 days but less than 20 years of age, who had sustained an arterial ischemic stroke and 306 control children without stroke matched for age, year of KPNC enrollment, and primary care facility.

Blood samples were unavailable for this study. Instead, to investigate the effect of infections on stroke risk, researchers used the total number of doctor visits during the 2 years before a stroke during which a diagnosis of 1 or more infections was made. They included only minor infections, excluding major ones associated with stroke, such as meningitis, sepsis, and endocarditis. And because the focus was on the 2 years before the stroke, they also excluded children whose stroke occurred before their second birthday.

A total of 74 cases (73%) and 187 controls (61%) had at least 1 visit for infection during the 2-year observation period. Dr. Fullerton noted that the spectrum of minor infections was remarkably similar between cases and controls and that the most common was upper respiratory tract infection. This type of infection represented 49.0% of infections in the cases and 45.4% of infections in the controls over the 2-year period.

The rate of infection before the stroke or index date was greater for cases than controls in each of 3 time periods: within 3 days, 4 to 7 days, and 8 to 30 days. After adjustment for these periods, sex, immunologic, hematologic, and cardiac disease, and head and neck trauma in the preceding month, a diagnosis of infection 3 days before a stroke conferred a 12-fold increased risk for arterial ischemic stroke (odds ratio, 12.1; 95% confidence interval, 2.5 - 56.7; P = .002).

The risk rapidly diminished after those 3 days, with no increased risk for stroke beyond 1 week.

The research showed that, unlike in adults, the cumulative number of infections over the 2-year period was not associated with stroke risk. That makes some sense as kids have negligible atherosclerosis and less time to accumulate chronic effects of infection.

One-Time Thing

"It seems to be kind of like a one-time thing; children have an infection and their stroke risk seem to go up, but then we don't have to be so worried about children having multiple infections over time," said Dr. Fullerton.

As for a causal pathway, a likely candidate, according to Dr. Fullerton, is infection-related activation of the coagulation cascade rather than arterial injury. Circulating inflammatory factors increase the risk for blood clots and possibly cause inflammation of the lining of the heart or blood vessels leading to the brain, she said.

It also might have something to do with exposure to cold remedies containing vasoactive ingredients or mechanical forces leading to cervical arterial dissection, she added. "If your blood vessels are inflamed and you have some sort of minor trauma like coughing or sneezing or play wrestling or diving into a pool, the vessels are just a bit more prone to injury."

The important message, she said, is that infection can be a trigger in children who are otherwise predisposed to stroke. "In some case, they are otherwise predisposed in ways we understand, like children who have congenital heart disease or sickle cell disease, but in other cases, they're predisposed in ways we don't understand," although genetics could play a role.

About half the kids who sustain a stroke were previously healthy, she said.

Overall, about 15% of children with stroke will go on to have a recurrence but in those with abnormalities of blood vessels to the brain, the recurrence rate of over 50%, said Dr. Fullerton.

Vaccinations may be an avenue toward avoiding stroke. In a large international prospective study of infection in childhood stroke, some results of which were presented earlier this year, Dr. Fullerton and her colleagues found that vaccinations are protective against childhood stroke. They also found that herpes infections are quite common in children with stroke, which is important because these infections can be treated with, for example, the antiviral acyclovir.

"This is one more reason that vaccination programs and good hygiene are so important in preventing infection," said Dr. Fullerton. She suggests that children at risk should get an annual flu shot.

And although aspirin, a mild blood thinner, has been linked to Reye's syndrome, "maybe aspirin isn't such a bad idea in kids with an infection," said Dr. Fullerton, adding that this idea is "certainly preliminary."

But also important is for parents — and physicians — to recognize that stroke really does happen to children, said Dr. Fullerton.

A limitation of the study was that while infectious exposure may be higher in children of low socioeconomic status, the Kaiser population lacks children in this demographic.

"Lively" Discussion

An accompanying editorial praises the study for being "well conducted," providing "interesting and novel information on an issue that so far has not been addressed in detail," and adding to the "ongoing and lively discussion" on why inflammatory processes may play an important role in thromboembolic events.

However, writes Lars Marquardt, MD, Department of Neurology, University of Erlangen-Nuremberg, Germany, the retrospective nature of the study poses some limitations. For one thing, many children don't seek medical attention for minor infections, so the true exposure might be underestimated. Also, no laboratory tests were available to determine the individual infectious burden, and there was no information on medications with possible antithrombotic effects.

It's also difficult to determine the effect of the study results on clinical practice, said Dr. Marquardt.

"Minor infections are common in children; strokes are rare. In this respect, despite these findings, there is no reason to be alarmed if a child catches a simple cold, a point worth emphasizing to parents," he concludes.

The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Fullerton is supported by National Institutes of Health grants and an American Heart Association Established Investigator Award. Dr. Marquardt has disclosed no relevant financial relationships.

Neurology. Published online August 20, 2014. Abstract Editorial

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